Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal conditions associated with immunocompromised solid organ and stem cell transplantation that can have 70-80% mortality (Gottschalk et al. (2005) Annu. Rev. Med. 56, 29-44; Paya et al. (1999) Transplantation 68, 1517-1525). PTLD is often associated with viral infection, such that latent viral infection of the transplanted material can cause complications in the transplant subject. For example, Epstein-Barr virus (EBV)-associated PTLD derives from herpes virus exposure that establishes latent infection in a majority of healthy adults. Proliferation of EBV-infected B cells in PTLD is maintained by expression of EBV latent genes, such as latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance. The incidence of PTLD varies according to the organ transplanted, as well as the intensity and duration of immunosuppression. In renal transplant recipients PTLD occurs in 1-2% of patients, but the incidence is as high as 20% in small bowel transplant and 1%-10% in lung, heart, liver, and kidney transplant recipients (Gottschalk et al. (2005) Annu. Rev. Med. 56, 29-44; Paya et al. (1999) Transplantation 68, 1517-1525). Children and transplant recipients without previously established anti-EBV immunity are among those at greatest risk for development of a PTLD. There is no accepted standard of therapy for PTLD, and the progression of the disease in patients is often not responsive to currently available therapies. Management of early PTLD lesions is currently based on reduction or withdrawal of immunosuppression which increases the risk of graft rejection.
In addition, cancer cells adapt to low oxygen tension by promoting the expression of genes associated with anaerobic metabolism, invasion and angiogenesis (Pugh et al. (2003) Nat Med 9, 677-684; Fraisl et al. (2009) Dev Cell 16, 167-179). The concerted action of hypoxia-regulated pathways allows tumor cells to sprout new vessels, co-opt host vessels and/or recruit angio-competent bone marrow-derived cells to generate functionally abnormal tumor vasculatures (Ferrara et al. (2005) Nature 438, 967-974). In spite of the well-established roles of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF), increasing evidence suggests the contribution of alternative ‘non-canonical’ pathways to hypoxia-driven neovascularization (Ferrara, N. (2010) Cytokine Growth Factor Rev 21, 21-26). This proposition is firmly grounded on emerging preclinical and clinical data demonstrating ‘evasive resistance’ or ‘intrinsic refractoriness’ to VEGF-targeted therapies, which fail to produce enduring clinical benefits (Ferrara, N. (2010) Cytokine Growth Factor Rev 21, 21-26; Ebos et al. (2009) Cancer Cell 15, 232-239; Paez-Ribes et al. (2009) Cancer Cell 15, 220-231).
The mechanisms underlying ‘evasive resistance’ involve revascularization as a result of the delivery of alternative pro-angiogenic signals (Bergers et al. (2008) Nat Rev Cancer 8, 592-603) and/or mobilization of bone marrow-derived inflammatory cells, which together with endothelial and pericyte progenitors, are recruited to the tumor vasculature (Shojaei et al. (2007) Nat Biotechnol 25, 911-920; Bergers et al. (2008) Nat Rev Cancer 8, 592-603). Future anti-angiogenic therapies might capitalize on an improved understanding of these compensatory pathways, as well as the elucidation of the molecular underpinnings of blood vessel normalization and the identification of hallmark signatures which distinguish healthy from tumor-associated endothelium (Jain, R. K. (2005) Science 307, 58-62). Although substantial changes in the endothelial cell (EC) surface ‘glycome’ were apparent under different culture conditions (Garcia-Vallejo et al. (2006) J Cell Physiol 206, 203-210; Willhauck-Fleckenstein et al. (2010) Angiogenesis 13, 25-42), suggesting a role for glycan structures in differentially regulating angiogenesis in hypoxic versus normoxic and in neoplastic versus healthy tissues, the specific glycan structures, mediating molecules, and mechanisms were not known prior to the results described herein.
Programmed remodeling of cell surface glycans can control cellular processes by displaying or masking ligands for endogenous lectins (Paulson et al. (2006) Nat Chem Biol 2, 238-248; van Kooyk et al. (2008) Nat Immunol 9, 593-601). Recent efforts involving genetic manipulation of N- and O-glycosylation pathways have revealed essential roles for multivalent lectin-glycan lattices in the control of receptor signaling (Ohtsubo, et al. (2006) Cell 126, 855-867; Dennis et al. (2009) Cell 139, 1229-1241; Dam et al. (2010) Glycobiology 20, 1061-1064). Regulated glycosylation can control sprouting angiogenesis by modulating binding of Notch receptor to its ligands Delta-like 4 (D114) or Jagged1 (Benedito et al. (2009) Cell 137, 1124-1135), fine-tuning neuropilin-1 (NRP-1) signaling (Shintani et al. (2006) EMBO J 25, 3045-3055) and facilitating CD31-mediated homophylic interactions (Kitazume et al. (2010) J Biol Chem 285, 6515-6521). Yet, whether differential glycosylation enables the formation of discrete lectin-glycan lattices and signaling clusters that are functionally relevant to angiogenesis remains largely unexplored.
In view of the above, it is clear that there remains a need in the art for compositions and methods to specifically boost host anti-viral (e.g., anti-EBV) immune responses, as well as inhibiting hypoxia associated angiogenesis in a number of disorders.